There are approximately 10 million wearers of prosthetic joints in the world today, and the number of prosthetic joint surgeries continues to increase each year, mainly because of population aging and of the increasing prevalence of obesity, which leads to an excess weight borne by the joints.
Accordingly, it is estimated that by 2020, 2.5 million individuals will undergo surgery to insert a prosthetic joint or to replace an existing prosthetic joint. Besides, an increase in the number of initial joint replacements done in young patients (i.e. under 50 years old) is also observed.
Current figures indicate that approximately 430,000 total hip and knee replacements are done each year in the United States, while approximately 130,000 total hip replacements (THR) and 100,000 total knee replacements (TKR) are implanted or replaced each year in France, where there are currently more than one million wearers of prosthetic joints.
Infection is one of the main complications of joint replacement surgery. In spite of the considerable progress recorded over recent years, prosthetic joint infections are still common, hovering between 0.3% and 2% for total hip replacements, and between 0.5% and 5% for total knee replacements, with the highest rates of infection occurring when existing prosthetic joints are replaced (from 3 days to nearly 20 years following surgery, with an average of 20% of infections occurring within 3 months of joint replacement; 40% occurring between 3 months and 2 years; and 40% occurring after 2 years). These infections are associated with a non-negligible mortality rate (2.5%) as well as with a high morbidity. They usually require one or several additional surgeries and a long course of antibiotics, resulting in significant and often lengthy functional disability. Eventually, the cost of managing these complications is very high, estimated at approximately 60,000 euros per prosthetic joint infection, thereby multiplying by four the cost price of a prosthetic joint when an infection occurs, e.g. reaching a total cost of approximately 80,000 euros for an infected prosthetic hip joint.
50% to 75% of prosthetic joint infections are caused by bacteria from the Staphylococcus family, sometimes in a mixed infection along with other species. The two principal species in question are Staphylococcus aureus and Staphylococcus epidermidis. Staphylococcal prosthetic joint infections are often dormant. The staphylococci assemble and form a biofilm on the surface of the prosthetic implant and survive in a quiescent state characterized by a low metabolic activity. The dormant state of the bacteria as well as the presence of the biofilm considerably reduce inflammatory reactions at the site of the infection and protect the bacteria from antibiotic action.
Prosthetic joint infections are currently managed following essentially two different strategies, namely either surgical debridement (cleaning-debriding) thereby preserving the prosthetic joint, or replacement of the prosthetic joint.
Surgical cleaning and debriding without removing the prosthetic joint (flushing with physiological serum and wound disinfectant), combined with appropriate long-course antibiotics is called for when the infection is detected early following contamination (less than 2 weeks) and when the prosthetic joint has not loosened. This strategy offers the best efficacy vs. risk ratio.
Indeed, where early detection cannot not be achieved, it is necessary to replace the prosthetic joint, either by a one-step or a two-steps replacement method. One-step replacement of the prosthetic joint is a less onerous intervention than the two-steps replacement that requires long hospital stays (6 weeks to 1 year), but it is less effective than the latter. Replacements of prosthetic joints are combined with an antibiotic treatment that is directed against the microorganism(s) that is or are likely to have caused the prosthetic joint infection. Surgical intervention for prosthetic joint infections is associated with mortality rates of 0.4 to 1.2% in 65-year-old patients and 2 to 7% in patients over 80 years old. The risk of the infection recurring remains high after a repeated intervention on a prosthetic joint infection, ranging on average from 10 to 40% according to the location, severity of the lesions and the type of surgical treatment used.
Accordingly, it is of the utmost importance, for the management of prosthetic joint infections, to establish a diagnosis of infection and to determine the causative microorganism as rapidly as possible.
In this regard, clinical symptoms are rarely sufficient to ascertain the infection. In the vast majority of cases, the symptoms simply alert the clinician to a problem and initiate additional examinations required for diagnosis.
Various methods are currently used for establishing the diagnosis of prosthetic joint infection as well as for identifying the causative agent.
Thus, inflammation biomarkers, such as the C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) are useful in the diagnosis of prosthetic joint infections. These techniques, however, do not have adequate sensitivity and specificity. Besides, a positive CRP level is not exclusive of a biopsy, since 10-15% of patients undergoing surgery have a normal CRP level. Accordingly, while assaying these biomarkers is prescribed by most surgeons, this mostly appears to be as much due to habit as to the absence of other more sensitive and specific tests taking advantage of serological markers.
Medical imaging techniques are also used. However, radiological diagnosis is not specific enough and only shows signs representative of the later phase of infections, such as loosening of the prosthesis, presence of nodules or cysts, etc. Scintigraphy, most frequently used with gallium, may be useful in diagnosis, but it is often difficult to interpret, thereby leading to a delayed detection of the infection. Magnetic Resonance Imaging and Computer Assisted Tomography scans are usually disregarded because of artifacts due to the presence of the prosthetic joint itself.
Histological analysis of samples obtained during surgery can also be performed. It allows infection to be diagnosed with a sensitivity (i.e. the capacity of detecting infected samples) above 80% and a specificity (i.e. the capacity of detecting non-infected samples) above 90%, but this of course requires a biopsy sample. Besides, depending on the sampling site, significant variations may be observed in the results obtained.
As such, the gold standard in diagnosing prosthetic joint infections remains bacteriological analysis, which involves isolation and culture of the infecting bacteria at the site of infection, from relevant samples. Bacteriological analysis is generally considered as significant if at least 2 out of 5 samples taken during surgery are positive for S. aureus and 3 out of 5 samples are positive for other staphylococci. Diagnosis based on samples obtained prior to surgery, e.g. by ultrasound-guided needle aspiration under local anesthesia, or image-guided core-needle biopsy in the operating room under general anesthesia can also be carried out.
Several well-known drawbacks are however associated to bacteriological analysis.
First of all, obtaining pre-operative samples or aspiration liquids for subsequent culture is an invasive procedure which usually requires a surgical procedure carried out under general anesthesia. Secondly, the specificity is often insufficient, since contaminant microorganisms may be isolated, particularly in the case of coagulase-negative staphylococci. Besides, positive results can be hindered due to the initiation of treatment with antibiotics. Thirdly, no standardized techniques have been established for culturing the samples and interpreting the results from the cultures (e.g. the threshold of at least 3 independent positive samples provides excellent specificity (99.6%), but is sometimes achieved to the detriment of sensitivity (65%)). Last but not least, the method may be time consuming since from 48 hours to over 2 weeks might be needed to obtain the results.
In order to overcome the drawbacks associated to bacteriological analysis, in particular as regards the long time needed to obtain the results, it has been suggested to use a serological approach based on the detection of anti-staphylococci antibodies.
Thus, tests to detect anti-α-toxin (or alpha antistaphylolysines), anti-α-ribitol teichoic acid and anti-capsule antibodies have been suggested for systemic infections with S. aureus (Bornstein et al. (1992) Med. Microbiol. Lett. 1:111-119; Christensson et al. (1993) J. Infect. Dis. 163:530-533). However, these tests have been abandoned due to inadequate sensitivity and specificity. In addition, the use of various staphylococcal protein antigens has been suggested for detecting antibodies directed against staphylococcal antigens (WO 2006/005825, U.S. Pat. No. 5,700,928, FR 2 908 890). Nevertheless, these markers, by themselves, do not provide for sufficient sensitivity and specificity. Accordingly, serological methods useful for diagnosing staphylococcal infections have yet to be implemented.